Liquid drug cartridges and associated dispenser

ABSTRACT

Liquid drug cartridges and an associated inhaler are used to deliver one more separate doses of an aerosolized liquid drug. A cartridge includes a container for storing the liquid drug, an end cap having an ejection opening, a filter element, and a piston that is repositionable relative to the container to selectively eject a volume of liquid drug from the ejection opening. The filter element filters the liquid drug prior to ejection from the ejection opening. The liquid drug cartridge can be coupled with an inhaler that includes an aerosol generator. The aerosol generator includes a vibratable membrane onto which the liquid drug is ejected. The liquid drug is aerosolized by the vibration of the membrane for inhalation by a user.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/009,704, filed Jun. 9, 2014, and claims the benefit of U.S.Provisional Application No. 62/099,806, filed Jan. 5, 2015, the contentsof which are incorporated herein by reference in their entirety for allpurposes.

BACKGROUND

Various types of inhalers exist for aerosolizing liquids. For example,U.S. Pat. No. 5,586,550, incorporated herein by reference, describes aninhaler that includes a dispensing apparatus in which a membrane withtapered apertures is vibrated such that liquid in contact with a rearface of the membrane is dispensed from a front face of the membrane asan aerosol.

While effective at nebulizing liquids, such inhalers may not beparticularly suited for certain applications, such as aerosolizing unitdoses of insulin for pulmonary delivery. Additionally, such inhalers mayemploy less than optimal methods with respect to liquid delivery to thedispensing apparatus, dose control, and microbial control.

Hence, improved approaches with respect to aerosolizing doses of insulinfor pulmonary delivery, liquid drug delivery to the dispensingapparatus, dose control, and/or microbial control between doses aredesirable.

BRIEF SUMMARY

Liquid drug cartridges and associated inhalers are provided. In manyembodiments, the cartridge includes a liquid drug container and a filterelement. The filter element is configured to filter the liquid drug inthe container prior to ejection from an ejection opening of thecontainer. The cartridge includes a piston that is moved relative to thecontainer to eject a volume of liquid from the container via theejection opening. In many embodiments, the cartridge and associatedinhaler are particularly suited for aerosolizing doses of insulin forpulmonary delivery. The liquid drug cartridge provides a convenient wayof supplying liquid drug to an aerosol generator. In many embodiments,the combination of the cartridge and the associated inhaler providesimproved control of dosage amount and improved suppression of microbialgrowth between doses.

Thus, in one aspect, a liquid drug cartridge is provided. The cartridgeincludes a container configured to store a liquid drug, an end capcoupled with a first end of the container, a filter element, and apiston. The end cap has an ejection opening from which a volume of theliquid drug from the container can be selectively ejected. The filterelement is configured to filter the liquid drug prior to ejection fromthe ejection opening. The piston seals a second end of the container.The piston is repositionable relative to the container so as toselectively eject a volume of the liquid drug from the container via theejection opening.

The cartridge can include additional elements and/or features. Forexample, the end cap can have a protruding portion in which the ejectionopening is disposed. The cartridge can include a removable capconfigured to interface with the end cap so as to block flow of theliquid drug through the ejection opening. The end cap can include aconduit in fluid communication with the ejection opening for delivery ofthe liquid drug to the ejection opening. The conduit can be coated toinhibit microbial ingress into the container. For example, the conduitcan be coated with, or made from, silver to inhibit microbial ingressinto the container.

The cartridge can be configured to inhibit escape of any amount of theliquid drug from the container absent repositioning of the pistonrelative to the container. For example, the conduit can be configured toinhibit escape of any amount of the liquid drug from the containerabsent repositioning of the piston relative to the container. Forexample, to prevent gravity induced flow of the liquid drug out of thecartridge in the absence of movement of the piston, the conduit can havea sufficiently small inner diameter relative to the surface tensionand/or viscosity of the liquid drug so as to inhibit flow of the liquiddrug through the conduit. The filter can also be configured to inhibitescape of any amount of the liquid drug from the container absentrepositioning of the piston relative to the container.

The cartridge can be configured to inhibit microbial ingress into thecontainer. For example, the conduit can be coated (e.g., with silver) toinhibit microbial ingress into the container. The filter element canalso be configured to inhibit microbial ingress into the container. Forexample, the filter element can incorporate one or more antimicrobialmaterials and/or compounds (e.g., silver).

In another aspect, an aerosolization system is provided. The system caninclude any of the liquid drug cartridge embodiments described herein,an aerosol generator including a vibratable membrane having a front faceand a rear face, a housing defining a mouthpiece, and an actuatorconfigured to reposition the piston relative to the container todispense a dosage of the drug via the ejection opening to the rear faceof the vibratable membrane. The aerosol generator includes a vibratableelement used to vibrate the vibratable membrane. The housing includes areceptacle configured to at least partially receive the cartridge andinterface with the cartridge to position the ejection opening todispense liquid drug directly onto the rear face of the vibratablemembrane to be aerosolized by controlled vibration of the vibratableelement.

The system can be configured such that the cartridge can be removed atany time to enable more thorough cleaning of the dispenser. When thecartridge is configured with a removable cap, the cap and the cartridgereceiving receptacle can be configured such that the cartridge cannot beinserted into the receptacle until the cap is removed from thecartridge.

In many embodiments, the housing is configured to provide a mixture ofair and aerosolized liquid drug for inhalation by a user. For example,the housing can include a mixing chamber in fluid communication with thefront face of the vibratable membrane and the mouthpiece and one or moreair inlets in fluid communication with the mixing chamber and configuredto inlet air into the mixing chamber in response to a user inhaling viathe mouthpiece. The system can further include an air flow restrictorarray having greater resistance to air flow than the one or more airinlets and placing the mixing chamber in fluid communication with theone or more air inlets. In many embodiments, the restrictor arrayincludes a plurality of orifices disposed in an annular arrangement. Inmany embodiments, the air flowing through the mixing chamber in responseto the user inhaling via the mouthpiece is laminar and surrounds adosage of the drug aerosolized via the vibratable membrane so as toinhibit contact between the aerosolized drug and surrounding surfaces ofthe mixing chamber. The system can include a pressure port connected toa pressure sensing system configured to detect a patient's inhalation.

The vibratable mesh can be coupled with the housing so as to enhanceefficiency of the aerosol generator. For example, the vibratable meshcan be coupled with the housing via suitable isolator members, forexample, elastomeric isolators.

The system can include an ultraviolet light source so as to providemicrobial control between doses. For example, one or more ultravioletlights sources can be used to irradiate a chamber of the housingdisposed between the rear face of the vibratable member and thecartridge and into which the drug is ejected from the cartridge via theejection opening.

In many embodiments, the housing is configured to retain the cartridgewithin the receptacle. Any suitable approach can be used to retain thecartridge within the receptacle. For example, the housing can beconfigured so as to form a pressurizable vessel that accommodates thecartridge. The actuator can be configured to pressurize the vessel toreposition the piston relative to the container to dispense a dosage ofthe drug via the ejection opening to the rear face of the membrane.Injection of air into the vessel can be controlled so as to dispense apredetermined desired amount of the liquid drug via the ejection openingfor aerosolization by the aerosol generator. For example, the piston canbe set slightly below the end of the container, creating a volume thatcan be pressurized by sealing against the end of the container or theinside wall of the container. As another example, the piston can behollowed out on the side opposite the liquid drug to create a volumethat can be pressurized. The pressurized volume will increase as liquidis dispensed. Removal (venting) of the air pressure can be used toimmediately stop the piston from further movement until the air pressureis re-applied.

In many embodiments, the actuator mechanically displaces the pistonrelative to the container so as to dispense a predetermined desiredamount of the liquid drug via the ejection opening for aerosolization bythe aerosol generator. The actuator can include an adjustable meteringmechanism that is operable to permit only selectable amounts ofrepositioning of the piston relative to the container so that aselectable dosage of the liquid drug is dispensed.

In many embodiments, the aerosolization system includes a control systemconfigured to control various aspects of the system. For example, thesystem can include one or more processors and a tangible memory storingnon-transitory instructions that, when executed by the one or moreprocessors, cause the one or more processors to control the actuator toaccomplish a priming cycle in which the actuator repositions the pistonrelative to the container until a drop of liquid has been ejected fromthe ejection opening. The instructions can be configured to cause theone or more processors to determine that a drop of the liquid has beenejected from the ejection opening by detecting when the vibratablemember has been wetted by the ejected drop of the liquid drug.

A self-puncturing liquid drug cartridge and associated inhaler are alsoprovided. In many embodiments, the cartridge includes a liquid drugcontainer and a needle assembly coupled to the container. Upon insertionof the cartridge into the associated inhaler, a hollow needle of theneedle assembly penetrates into the cartridge, thereby establishing afluid path by which the liquid drug within the container can be ejectedfor aerosolizing by the inhaler. In many embodiments, the cartridge andassociated inhaler are particularly suited for aerosolizing doses ofinsulin for pulmonary delivery. The self-puncturing liquid drugcartridge provides a convenient way of supplying liquid drug to anaerosol generator. In many embodiments, the combination of the cartridgeand the associated inhaler provides improved control of dosage amountand improved suppression of microbial growth between doses.

Thus, in one aspect, a self-puncturing liquid drug cartridge isprovided. The cartridge includes a container configured to store aliquid drug, a septum configured to seal a first end of the container; aneedle assembly coupled to the first end of the container, and a pistonsealing a second end of the container. The needle assembly includes ahollow needle and is reconfigurable between a first configuration inwhich the hollow needle does not extend through the septum and a secondconfiguration in which the hollow needle extends through the septum. Thepiston is repositionable relative to the container so as to selectivelyeject a volume of the liquid drug from the container via the hollowneedle.

In many embodiments, the needle assembly includes a cap configured tocouple the needle assembly with the container. For example, the cap caninclude a receptacle shaped to receive and retain an end portion of thecontainer (e.g., via complementarily-shaped surfaces providing a snapfit coupling between the cap and the end portion of the container). Inmany embodiments, the cap includes an aperture configured to accommodatea portion of the hollow needle and movement of the of the hollow needleduring reconfiguration of the needle assembly from the firstconfiguration to the second configuration. In many embodiments, there isan elastomeric seal disposed between the cap and the end portion of thecontainer. The elastomeric seal prevents the liquid from leaking outfrom the container and prevents ingress of microbiological organisms andother contaminants.

In many embodiments, the needle assembly includes a guide element. Theguide element can be configured to support the hollow needle in a fixedposition and orientation relative to the guide element. The guideelement can be configured to guide movement of the hollow needlerelative to the container during reconfiguration of the needle assemblefrom the first configuration to the second configuration. The guideelement can include a receptacle configured to receive the cap and aportion of the container and interface with at least one of the cap andthe portion of the container so as to constrain relative movementbetween the container and the guide element to translation parallel tothe hollow needle. In many embodiments, an end of the hollow needle fromwhich the liquid drug is ejected protrudes from an end surface of theguide element by a predetermined controlled distance.

In many embodiments, the needle assembly includes a spring elementconfigured to bias the needle assembly into the first configuration inthe absence of induced displacement of the container relative to theguide element. For example, the needle assembly can include a coilspring disposed within the guide element receptacle and between an endwall of the guide element receptacle and the needle assembly cap. In theabsence of induced displacement of the container and cap relative to thereceptacle of the guide element, the spring is in an un-deformedconfiguration and the needle assembly is in the first configuration inwhich the hollow needle does not extend through the septum. By inducingdisplacement of the container and cap further into the receptacle of theguide element, the spring can be compressed sufficiently such that theneedle assembly is reconfigured into the second configuration in whichthe hollow needle extends through the septum, thereby providing a fluidpath for the liquid drug in the container to be ejected from thecartridge via the hollow needle.

In many embodiments, the guide element includes a feature to prevent thespring from pushing it off the cap. For example, the guide element caninclude a protruding feature on the inside surface of the guide elementthat slides in a slot on the outside surface of the cap. The slot can befurther configured in the shape of a capital “L” to lock it in the firstconfiguration for shipment. The patient would be required to twist theguide element before use to unlock it and allow the protruding featureto slide in the axial direction of the cap. Alternatively, the ends ofspring can be mechanically fixed to the guide element and the cap toprovide retention of these pieces. In many embodiments, the springmaintains a consistent and specific distance between the outlet of theneedle and the back side of an aerosol generating mesh so as to preventcontact between the needle and the mesh but still close enough totransfer liquid droplets onto the mesh.

In many embodiments, the hollow needle is coated to inhibit microbialingress into the hollow needle and the container. For example, theneedle can be coated with silver to inhibit microbial growth and/oringress. As another example, the self-puncturing liquid drug cartridgecan include a filter configured to inhibit microbial ingress into thecontainer.

In another aspect, an aerosolization system is provided. The system caninclude any of the self-puncturing liquid drug cartridge embodimentsdescribed herein, a housing defining a mouthpiece, an aerosol generatordisposed in the housing, and an actuator configured to reposition thecartridge piston relative to the container to dispense a dosage of theliquid drug via the hollow needle to the aerosol generator. The housingincludes a receptacle configured to at least partially receive thecartridge and interface with the needle assembly such that the needleassembly is reconfigured from the first configuration to the secondconfiguration during an insertion of the cartridge into the receptacle.The aerosol generator includes a vibratable membrane having a front faceand a rear face, and a vibratable element used to vibrate the membrane.The actuator is configured to reposition the piston relative to thecontainer to dispense a dosage of the drug via the hollow needle to therear face of the vibratable membrane. The system can be configured suchthat the cartridge can be removed at any time to enable more thoroughcleaning of the dispenser. When the cartridge is configured with aremovable cap, the cap and the cartridge receiving receptacle can beconfigured such that the cartridge cannot be inserted into thereceptacle until the cap is removed from the cartridge.

In many embodiments, the housing is configured to provide a mixture ofair and aerosolized liquid drug for inhalation by a user. For example,the housing can include a mixing chamber in fluid communication with thefront face of the vibratable membrane and the mouthpiece and one or moreair inlets in fluid communication with the mixing chamber and configuredto inlet air into the mixing chamber in response to a user inhaling viathe mouthpiece. The system can further include an air flow restrictorarray having greater resistance to air flow than the one or more airinlets and placing the mixing chamber in fluid communication with theone or more air inlets. In many embodiments, the restrictor arrayincludes a plurality of orifices disposed in an annular arrangement. Inmany embodiments, the air flowing through the mixing chamber in responseto the user inhaling via the mouthpiece is laminar and surrounds adosage of the drug aerosolized via the vibratable membrane so as toinhibit contact between the aerosolized drug and surrounding surfaces ofthe mixing chamber. The system can include a pressure port connected toa pressure sensing system configured to detect a patient's inhalation.

The vibratable mesh can be coupled with the housing so as to enhanceefficiency of the aerosol generator. For example, the vibratable meshcan be coupled with the housing via suitable isolator members, forexample, elastomeric isolators.

The system can include an ultraviolet light source so as to providemicrobial control between doses. For example, one or more ultravioletlights sources can be used to irradiate a chamber of the housingdisposed between the rear face of the vibratable member and thecartridge and into which the drug is ejected from the cartridge via thehollow needle.

In many embodiments, the housing is configured to retain the cartridgewithin the receptacle. Any suitable approach can be used to retain thecartridge within the receptacle. For example, the housing can beconfigured so as to form a pressurizable vessel that accommodates thecartridge. The actuator can be configured to pressurize the vessel toreposition the piston relative to the container to dispense a dosage ofthe drug via the hollow needle to the rear face of the membrane.Injection of air into the vessel can be controlled so as to dispense apredetermined desired amount of the liquid drug via the hollow needlefor aerosolization by the aerosol generator. For example, the piston canbe set slightly below the end of the container, creating a volume thatcan be pressurized by sealing against the end of the container or theinside wall of the container. As another example, the piston can behollowed out on the side opposite the liquid drug to create a volumethat can be pressurized. The pressurized volume will increase as liquidis dispensed. Removal (venting) of the air pressure can be used toimmediately stop the piston from further movement until the air pressureis re-applied.

In many embodiments, the actuator mechanically displaces the pistonrelative to the container so as to dispense a predetermined desiredamount of the liquid drug via the hollow needle for aerosolization bythe aerosol generator. The actuator can include an adjustable meteringmechanism that is operable to permit only selectable amounts ofrepositioning of the piston relative to the container so that aselectable dosage of the liquid drug is dispensed.

In many embodiments, the aerosolization system includes a control systemconfigured to control various aspects of the system. For example, thesystem can include one or more processors and a tangible memory storingnon-transitory instructions that, when executed by the one or moreprocessors, cause the one or more processors to control the actuator toaccomplish a priming cycle in which the actuator repositions the pistonrelative to the container until a drop of liquid has been ejected fromthe hollow needle. The instructions can be configured to cause the oneor more processors to determine that a drop of the liquid has beenejected from the hollow needle by detecting when the vibratable memberhas been wetted by the ejected drop of the liquid drug.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional view of a liquid drug cartridge, inaccordance with many embodiments.

FIG. 2 is a cross-sectional view illustrating an inhaler into which adrug cartridge is inserted, in accordance with many embodiments.

FIG. 3 is a cross-sectional view illustrating the drug cartridge of FIG.1 inserted into the inhaler of FIG. 2 and retained by an end member, aswell as liquid drug ejected from the cartridge being aerosolized forinhalation by a user, in accordance with many embodiments.

FIG. 4 is an end view illustrating a flow restricting array of orificesof the inhaler of FIG. 2, in accordance with many embodiments.

FIG. 5 is a simplified schematic diagram illustrating components of aninhaler configured to receiving liquid drug from a drug cartridge, inaccordance with many embodiments.

FIG. 6 is a cross-sectional view of another liquid drug cartridge, inaccordance with many embodiments.

FIG. 7 is a cross-sectional view of a liquid drug cartridge thatincludes a check valve, in accordance with many embodiments.

FIG. 8 is a cross-sectional view illustrating the drug cartridge of FIG.7 inserted into the inhaler of FIG. 2, as well as liquid drug ejectedfrom the cartridge being aerosolized for inhalation by a user, inaccordance with many embodiments.

FIG. 9 is a partial cut-away side view of a self-puncturing liquid drugcartridge, in accordance with many embodiments.

FIG. 10 is a partial cross-sectional side view of a removable capcoupled with an end of the drug cartridge of FIG. 9, in accordance withmany embodiments.

FIG. 11 is a side view illustrating the drug cartridge of FIG. 9partially inserted into the inhaler of FIG. 2, in accordance with manyembodiments.

FIG. 12 is a side view illustrating the drug cartridge of FIG. 9inserted into the inhaler of FIG. 2 to a depth sufficient to result inpenetration of a hollow needle through a septum so as to establish afluid path for ejection of liquid drug from the cartridge, in accordancewith many embodiments.

FIG. 13 is a side view illustrating the drug cartridge of FIG. 9 fullyinserted into the inhaler of FIG. 2 and retained by an end member, aswell as liquid drug ejected from the cartridge being aerosolized forinhalation by a user, in accordance with many embodiments.

FIG. 14 is a side view of another self-puncturing liquid drug cartridgepartially inserted into the inhaler of FIG. 2, in accordance with manyembodiments.

FIG. 15 is a side view illustrating the self-puncturing liquid drugcartridge of FIG. 14 inserted into the inhaler of FIG. 2 to a depthsufficient to result in penetration of a hollow needle through a septumand into a filter so as to establish a fluid path for ejection of liquiddrug from the cartridge, in accordance with many embodiments.

DETAILED DESCRIPTION

Liquid drug cartridges and an associated inhaler are described herein.In many embodiments, a cartridge containing a drug formulation isinserted into a dispenser until the cartridge contacts a shelf of thedispenser. In many embodiments, a continuous dispensing of formulationis possible, as well as very small and very large doses from the samecartridge.

The cartridge can be biased into contact with a mating surface of theinhaler to ensure precise and close positioning of the ejection openingrelative to a vibratable membrane of the inhaler so that when a dropletof liquid drug is dispensed via the ejection opening, surface tensionwill cause it to it will adhere to the vibratable membrane even when theinhaler is in a horizontal orientation. The adherence is controlled bythe distance between the ejection opening and vibratable membrane, theinside diameter of the ejection opening, and the geometry of theejection opening where the droplet exits.

The membrane vibrates to generate an aerosol and creates a pumpingaction that pulls the droplet away from the ejection opening and throughthe membrane. At the end of a dose, there is no residual droplet to beaerosolized due to the pumping action of the membrane. In manyembodiments, elastomeric isolators are used to couple the vibratablemembrane with a housing of the inhaler to maximize efficiency of theaerosol generation.

In many embodiments, as the patient inhales, air flows through airinlets into a manifold and then passes through a restrictor array. Theair flow transports the aerosol to the patient. In many embodiments, theair inlet have significantly less resistance than the restrictor array.A pressure port and associated pressure sensor can be incorporated todetect the strength of a patient's inhalation.

The cartridge can be configured to inhibit microbial ingress into theliquid drug container. For example, the end cap can include a conduitthat is coated, for example with silver, to discourage microbial ingressinto the conduit and the liquid drug container. In many embodiments,there is no retrograde flow back into the container after a dose isdispensed (i.e., any drug in the conduit there in contact with theantimicrobial coating to suppress pathogen proliferation). The liquiddrug cartridge can include a filter configured to inhibit microbialingress into the container.

The cartridge is configured to protect the user against accidentalneedle stick. For example, the ejection opening can be integrally formedinto the end cap, thereby avoiding the use of a needle. A removableprotective cap can be used to protect the ejection opening from damageand contamination. The protective cap can be shaped such that that thecartridge cannot be inserted into the inhaler until the protective capis removed.

The cartridge include a piston slidably disposed within the containerfor dispensing the liquid drug without the introduction of air. Thisfeature improves physical stability of the drug product, supports use ofthe cartridge in a horizontal orientation, and maintains the containerin a sealed configuration at all times for consistent dosing.

Any suitable approach for actuating the piston can be used. For example,the piston can be air driven by incorporating a seal between the endmember and the housing of the inhaler or it can be mechanically drivenvia an actuation mechanism coupled with the end member or passingthrough the end member.

A priming cycle can be used to eject air from the container and/or theejection opening. For example, after a cartridge is loaded into anassociated inhaler, a mechanical plunger can be brought into contactwith and push the piston until a drop of formulation is dispensed. Thiscan be sensed by aerosol generator software, which can be configureddetect the difference between a wet and dry vibratable membrane.

An inhaler can incorporate additional microbial control features. Forexample, an ultraviolet light can be added in a chamber where thedroplet is ejected from the ejection opening so as to provide additionalmicrobial control between doses.

The cartridge and the inhaler can be configured such that the cartridgecan be removed and reinserted at any time. For example, the cartridgecan be removed at any time to enhance access for cleaning the inhaler.In many embodiments, reinsertion of the cartridge induces a primingcycle.

In many embodiments, an inhaler includes a housing defining a dispensingoutlet, a vibratable membrane having a front face exposed at the outletand a rear face for receiving a liquid to be dispensed, and a vibratingmechanism connected to the housing and operable to vibrate the membraneto dispense aerosol of the liquid through the membrane. A liquiddelivery system is used to deliver a metered quantity of the liquid tothe rear face of the membrane. In this way, a metered quantity of liquidis dispensable at the outlet by operating the vibrating mechanism for anoperating period sufficient to completely aerosolize the meteredquantity of liquid delivered to the rear face of the vibratable member.

An advantage of such an apparatus is that it facilitates the dispensingof substantially all of the liquid coming into contact with the rearface of the membrane as a single dose, especially when the metered doseis relatively small in volume. By dispensing the entire dose, themembrane is essentially free of liquid from one dose to the next. Inthis way, it is thereby possible to avoid contact between liquid andambient air during periods of non-use between successive uses. Forpharmaceutical preparations this is particularly important since it mayobviate the need for the use of preservatives in the liquid and avoidsevaporative losses. For example, various preservative free insulinformulations that may be used include those described in U.S.application Ser. No. 13/004,662, entitled “Preservative Free InsulinFormulations and Systems and Methods for Aerosolizing” and in U.S.Provisional Application No. 62/120,573, entitled “Liquid InsulinFormulations,” each of which is hereby incorporated by reference in itsentirety.

Such an apparatus is particularly useful in the administration ofinhaled pharmaceutical liquid products where it is required that a fineaerosol of liquid be entrained in an inhaled air flow passing throughthe mouthpiece. One example of such a liquid is an insulin composition.

In many embodiments, the cartridge is a multi-dose cartridge. Forexample, the cartridge may contain enough medication for a day, a week,or a month's worth of treatment. The volume of the dose dispensed fromthe cartridge can be controlled via any suitable approach, such as viapositioning of the piston. The position of movement of the piston can beset by an external control. For example, the piston can be moved insmall enough increments to eject a very small volume of liquid, forexample 10 μL of liquid, or a large volume of liquid, for example 1000μL of liquid, thereby delivering a small or large amount of medication.The position of the piston can be maintained in a fixed location afterdosing, until a future dose is required. To dispense subsequent doses,the piston can be moved through subsequent positions to deliveradditional doses until the cartridge is empty.

Turning now to the drawings in which like numbers reference likecomponents, FIG. 1 illustrates a liquid drug cartridge 10, in accordancewith many embodiments. The cartridge 10 includes a container assembly12, an end cap assembly 14, and a filter 16.

The container assembly 12 is configured to store a liquid drug forsubsequent dispensing to an inhaler. The container assembly 12 includesa container 18 having openings at opposing ends of the container 18. Theend cap assembly 14 seals a first end of the container 18. A piston 20seals a second end of the container 18. The piston 20 is selectivelyslidable within the container 18 so as to eject a selected quantity ofthe liquid drug from the container 18.

The end cap assembly 14 has an ejection opening 22 from which the liquiddrug is ejected. In many embodiments, the end cap assembly 14 isconfigured so that the ejection opening 22 is located at the end of aprotruding portion of the end cap assembly 14 so as to be located at aprecise location relative to an interface surface 24 of the end capassembly 14.

The end cap assembly 14 includes an end cap body 26, a conduit 28, and aremovable cover 30. The cover 30 can be configured to provide amicrobial barrier prior to the first use of the cartridge. Thismicrobial barrier could be achieve by sealing against the end capassembly 14 or by integrating the cover 30 and end cap assembly 14 intothe one piece that is separated as the cap is removed. The end cap body26 can be made from a suitable material (e.g., a suitable resilientmaterial) and be shaped to interface with complementarily shaped endportion of the container 18. In the illustrated embodiment, the conduit28 is a cylindrical metal component having a suitable inside diameter.For example, the inside diameter of the conduit 28 can be selected to belarge enough to allow controlled flow of the liquid drug when the pistonis controllably displaced relative to the container 18 yet small enoughto inhibit flow of the liquid drug in the absence of movement of thepiston 20 relative to the container 18.

The filter 16 is configured to filter the liquid drug ejected from thecontainer 18 prior to passing through the conduit 28. In the illustratedembodiment, the filter 16 has a cylindrical body made from a suitablefilter material. For example, a sintered polyethylene filter with poresize of 0.2 to 100 μm or a thin membrane composed of Nylon, PTFE,polypropylene, or other material that is compatible with the liquid drug10. This filter may be designed to resemble a syringe filter. Controlledmovement of the piston 20 relative to the container 18 is used to induceflow of the liquid drug in the container through the filter 16. Afterpassing through the filter 16, the liquid drug passes through theconduit 28 to exit via the ejection opening 22. The filter 16 can beconfigured to inhibit flow of the liquid drug into the conduit 28 in theabsence of movement of the piston relative to the container 18.

FIG. 2 shows a cross-sectional view of an inhaler 40, in accordance withmany embodiments, that is configured to use the cartridge 10. Theinhaler 40 includes a housing 42 and an aerosol generator 44 mounted tothe housing 42 via isolators 46. The housing 42 forms a receptacle 48configured to slidingly receive the cartridge 10. An inner surface 50 ofthe receptacle 48 is configured to interface with the exterior surfaceof the cartridge 10 such that the cartridge 10 is constrained toslidingly translate relative to the receptacle 48. The interface surface24 of the end cap assembly 14 contacts a shelf 52 of the inhaler 40 soas to position the ejection opening 22 in a fixed position relative tothe aerosol generator 44.

The aerosol generator 44 includes a vibratable membrane having a frontface 54 exposed to an outlet duct 56 and a rear face 58 contacted in useby liquid ejected from the cartridge 10. The aerosol generator 44 ismounted to the housing 42 by the isolators 46 and is operable todispense an active pharmaceutical agent as an aerosol through amouthpiece 60. Exemplary aerosol generators that can be used are alsodescribed in U.S. Pat. Nos. 5,164,740; 6,629,646; 6,926,208; 7,108,197;5,938,117; 6,540,153; 6,540,154; 7,040,549; 6,921,020; 7,083,112;7,628,339; 5,586,550; 5,758,637; 6,085,740; 6,467,476; 6,640,804;7,174,888; 6,014,970; 6,205,999; 6,755,189; 6,427,682; 6,814,071;7,066,398; 6,978,941; 7,100,600; 7,032,590; 7,195,011, incorporatedherein by reference. These references describe exemplary aerosolgenerators, ways to manufacture such aerosol generators and ways tosupply liquid to aerosol generators, and are incorporated by referencefor at least these features. The aerosol generators may comprisevibratable membranes having tapered aperture with a size in the rangefrom about 3 μm to about 8 μm, preferably from about 3 μm to about 6 μm,and in some cases around 4 μm. The membrane may be domed shaped and bevibrated by an annular piezoelectric element that circumscribes theapertures. The diameter of the membrane may be in the range from about 5mm to about 8 mm. The membrane may also have a thickness in the rangefrom about 50 microns to about 70 microns. Typically, the membrane willbe vibrated at a frequency in the range from about 50 kHz to about 150kHz.

FIG. 3 illustrates the cartridge 10 installed into the inhaler 40. Anend member 66 retains the cartridge 10 so as to maintain contact betweenthe interface surface 24 of the end cap assembly 14 and the shelf 52 ofthe inhaler 40, thereby precisely controlling the position of theejection opening 22 relative to the rear face 58 of the vibratablemembrane.

The inhaler 40 can include a suitable actuator for displacing the piston20 relative to the container 18 so as to eject a desired preselecteddose of liquid drug from the container 18 via the ejection opening 22.For example, the end member 66 and the housing 42 can form apressurizable vessel into which air can be injected so as to displacethe piston 20 towards the ejection opening 22. As another example, thepiston 20 can be controllably displaced toward the ejection opening 22via an actuation mechanism coupled with the end member 66 or actingthrough the end member 66.

In use, a user inhales from the mouthpiece 60 and the aerosol generator44 simultaneously aerosolizes a dose of liquid drug ejected from theejection opening 22 via a corresponding actuation of the piston 20. Thehousing 42 includes one or more air inlets 68 and a restrictor array 70by which air is introduced into a mixing chamber 72 for combination withthe aerosolized dose of the liquid drug prior to inhalation by the user.

FIG. 4 shows an end view of the restrictor array 70, which includes anannular arrangement of orifices 74. The orifices 74 are sized such thatthe user inhalation occurs over a sufficient period of time for theliquid drug dose to be suitably aerosolized. In many embodiments, theone or more air inlets 68 have significantly less resistance to airflowthan the restrictor array 70. In many embodiments, the restrictor array70 is configured to produce laminar airflow that surrounds the resultingflow of the aerosolized liquid drug, thereby inhibiting and even largelypreventing contact between the aerosolized drug and surfaces of themixing chamber 72.

In many embodiments, the inhaler 40 includes an ultraviolet light sourceconfigured to illuminate at least a portion of a chamber 76 into whichthe ejecting end of the hollow needle 16 ejects the liquid drug. Theultraviolet light source can be used to provide increased microbialcontrol, for example, in the time periods between doses.

In many embodiments, the inhaler 40 includes a pressure port 78 that iscoupled to a pressure sensing system to detect a patient's inhalation.For example, the pressure sensor can be used to determine when a patientstarts breathing so as to start the aerosol generator and when thepatient stops breathing so as to pause generation to prevent waste,maximize dose efficiency, and maintain consistent delivery.

FIG. 5 shows a simplified schematic diagram of components of the inhaler40. The inhaler 40 includes control electronics 80, input/outputdevice(s) 82, the aerosol generator 44, an inhalation strengthmonitoring system 84, an ultraviolet light source 86, a piston actuationsystem 88, one or more batteries 90, and/or an external port 92. Thecontrol electronics 80 are operatively coupled with the input/outputdevice(s) 82, the aerosol generator 44, the inhalation strengthmonitoring system 84, the ultraviolet light source 86, the pistonactuation system 88, the one or more batteries 90, and/or the externalport 92.

Any suitable configuration of the control electronics 80 can be used.For example, in the illustrated embodiment, the control electronics 80include one or more processors 94 and a tangible memory 96. The memory96 can include read only memory (ROM) 98 and/or random access memory(RAM) 100. The memory 96 stores instructions that, when executed by theone or more processors 94, cause the processor(s) to control theoperation of the various subsystems of the inhaler 40.

For example, the instructions can be configured to cause the controlelectronics 80 to receive input from a user via the input/output devices82 regarding a desired dose of liquid drug to be dispensed by theinhaler 40. The control electronics 80 can receive a signal from theinhalation strength monitoring system 84 indicative of inhalation viathe inhaler 40 by the user. In response to the signal indicatinginhalation by the user, the control electronics can cause the actuationsystem 88 to eject a dose of liquid drug to the aerosol generator 44 andcause the aerosol generator 44 to aerosolize the ejected dose concurrentwith the detected inhalation by the patient. In response to the signalindicating when the patient stops inhaling, the control electronics canbe configured to pause the aerosol generation.

Any suitable configuration of the input/output device(s) 82 can be used.For example, the input/output device(s) 82 can include input buttons anda display device, such as an LCD screen and/or one or more indicatorlights.

The inhalation monitoring system 84 can include a pressure transduceroperatively coupled to the pressure port 78. The pressure transduceroutputs a signal to the control electronics 80 indicative of thepressure at the pressure port 78. The control electronics 80 can beconfigured to monitor the pressure signal from the pressure transducerso as to detect reduced pressure associated with airflow through theinhaler induced by a user's inhalation.

The ultraviolet light source 86 can be energized periodically for anysuitable length of time so as to provide microbial control betweendoses. The ultraviolet light source can be selected to provide anappropriate wavelength spectrum to kill microbes. For example, thecontrol electronics 80 can be configured to energize the ultravioletlight source 86 in accordance with a predetermined schedule followingthe administration of any particular dose.

The one or more batteries 90 can be connected to the various subsystemsof the inhaler in any suitable fashion. For example, the one or morebatteries 90 be directly wired any particular subsystem with the controlelectronics 80 being connected to control an associated switch used tocontrol the supply of power from the one or more batteries 90 to theparticular subsystem. The one or more batteries 90 can be replaceableand/or rechargeable.

In embodiments where the one or more batteries 90 are rechargeable,recharging can be accomplished via the external port 92. The externalport 92 can also be used to transfer data to and/or from the controlelectronics 80, for example, program instructions and/or operationalparameters for operational control of the inhaler 40 and/or inhaler usedata that is output to an external system for review and/or analysis.

The inhaler 40 can be operated to deliver a metered quantity of theliquid drug from the cartridge 10 to the rear face 58 of the vibratablemembrane 64. Hence, for each use a metered quantity of aerosolizedpharmaceutical agent can be dispensed at the mouthpiece 60 outlet byoperation of the aerosol generator 44.

The cartridge 10 contains a reservoir of active pharmaceutical agent,from which a predetermined does of the agent can be dispensed. Forexample, a dose of between about 80 to about 120 micro-liters ofinsulin. The lower limit is typically at least about 15 micro-liters andthe upper limit is typically about 1,000 micro-liters to about 2,000micro-liters. One particularly useful range is about 80 micro-liters toabout 120 micro-liters in a concentration of about 100 insulin units/mlor greater, and more preferably between about 200-800 units/ml, and insome cases as high as 2,500 units/ml.

The conduit 28 provides a fluid passage for the liquid drug to thevibratable membrane 64. The ejection opening 22 is positioned in closedproximity to rear face 58 of the vibrating membrane 64. Typically, theejection opening 22 will be less than 5 mm and more preferably less than2 mm from the rear face 58. The conduit 28 can be made of, for example,stainless steel alloy type 316 with a gage size ranging from 22 gage to26 gage.

When the cartridge 10 is installed in the inhaler 40, an indicator lightcan start to blink signaling to the patient that the inhaler 10 is readyfor use. At any time shortly thereafter the patient may inhale throughthe mouthpiece 60. Patient inhalation is detected by a flow sensor. Thedetection of patient inhalation results in activation of the aerosolgenerator 44 to produce aerosol particles into the mixing chamber 56.Aerosol is entrained in the inhalation air flow and flows via therespiratory system to the lungs of the patient. When the entire dose isaerosolized, which may take one or more breaths, an “end-of-dose”indicator light can be illuminated a second time to signal the patientthat the entire dose has been delivered. Delivery of the entire dose isobtained when at least about 95% of the dose is delivered, morepreferably 98% and most preferably when more than 99% of the dose isdelivered. To receive the dose, the patient may take several inhalationsor a single inhalation depending on the volume of liquid drug deliveredto the vibrating membrane 64 and the patient's breathing capacity. Eachinhalation should be a deep breath to assure that the aerosol reachesdeeply to the lungs.

The inhaler can be configured to accommodate cleaning and/orsterilization of the vibratable membrane and/or the chamber into whichthe cartridge 10 ejects the liquid drug. The inhaler can include airvents and/or drain features so that a cleaning fluid (e.g., water or anysuitable fluid) can be introduced to and removed from the chamber intowhich the cartridge 10 ejects the liquid drug. The control electronicscan be sealed in one or more separate compartments to avoid contact withthe cleaning fluid. A cleaning cartridge containing a cleaning fluid(e.g., water or any suitable fluid) can be occasionally installed toclean the mesh. The pressure sensing can be reversed to turn the inhaleroff if someone tries to inhale the water vapor. There can be a “soak”mode where the water droplet is allow to sit on the mesh with anoccasional vibration, for example, providing an alternating soak, rinse,soak, rinse cycle. A simpler configuration would employ a plastic funnelwith a small opening at the tip that the patient would insert into thecartridge slot and drip water into the inhaler. The small opening can beconfigured to limit the amount of water to a slow drip.

FIG. 6 illustrates another liquid drug cartridge 110, in accordance withmany embodiments, that can be used with an inhaler (e.g., the inhaler40). The cartridge 110 includes a container 112, a filter 16, an end cap114, and a removable cover 116. The end cap 114 has a protruding portion118 that provides a fluid conduit 120 and an ejection opening 22 fromwhich the liquid drug is ejected to the rear face 58 of the vibratablemembrane 64. As with the fluid conduit 28, the inside diameter of theconduit 120 can be selected to be large enough to allow controlled flowof the liquid drug when the piston 20 is controllably displaced relativeto the container 112 yet small enough to inhibit flow of the liquid drugin the absence of movement of the piston 20 relative to the container112. The inside of the conduit 120 can be coated (e.g., with silver) toinhibit the ingress of microbes into the cartridge 110.

FIG. 7 illustrates another liquid drug cartridge 210, in accordance withmany embodiments. The cartridge 210 is configured similar to thecartridge 10 but includes a check valve 212 in addition to the containerassembly 12 and the end cap assembly 14 described herein with respect tothe cartridge 10. Although not included in the illustrated embodiment,the liquid drug cartridge 210 can further include a filter element suchas the filter element of the drug cartridge 10. For example, one or morefilters the same or similar to the filter 16 can be disposed upstream ofthe check valve 212 and/or downstream of the check valve 212.

In many embodiments, the check valve 212 is configured to provide aphysical barrier against microbial ingress into the liquid drug storedwithin the container 18. Any suitable configuration can be used for thecheck valve 212 to ensure only one-way flow of the liquid drug from thecontainer 18 to the conduit 28. For example, the check valve 212 can bea duckbill valve or a mechanical valve such as a spring loaded ballvalve. Opening and closing of the check valve 212 can be controlled bypressure within the container 18 as a result of actuation of the piston20 as described herein. The check valve 212 can be mechanically actuatedand/or electrically actuated. Example suitable check valveconfigurations that can be employed are described in U.S. Pat. Nos.5,759,101 and 6,089,260; and in U.S. Patent Publications 2015/0048119and 2012/0041381; the full disclosures of which are hereby incorporatedby reference herein.

FIG. 8 illustrates the cartridge 210 installed into the inhaler 40. Theend member 66 retains the cartridge 210 so as to maintain contactbetween the interface surface 24 of the end cap assembly 14 and theshelf 52 of the inhaler 40, thereby precisely controlling the positionof the ejection opening 22 relative to the rear face 58 of thevibratable membrane.

As described herein, in many embodiments the inhaler 40 is configured tocontrollably displace the piston 20 relative to the container 18.Displacing the piston 20 relative to the container 18 can be used toincrease the pressure within the container 18 so as to open the checkvalve 212 to eject a desired preselected dose of liquid drug from thecontainer 18 via the ejection opening 22 for inhalation by a user asdescribed herein.

Self-Puncturing Liquid Drug Cartridges

Embodiments of self-puncturing liquid drug cartridges are also describedherein. In many embodiments, a self-puncturing liquid drug cartridgecontaining a drug formulation is inserted into a dispenser until a guideelement of the cartridge contacts a shelf of the dispenser. When thecartridge is further inserted into the dispenser, a cap and containerassembly of the cartridge slides inside the guide element and againstthe sharpened end of a hollow needle of the cartridge. The hollow needlepunctures a septum so as to establish a fluid path for ejection of theliquid drug from the container of the cartridge for aerosolization bythe inhaler for inhalation by a user. In many embodiments, a continuousdispensing of formulation is possible, as well as very small and verylarge doses from the same cartridge.

The cartridge includes a spring that assures that the guide elementremains in contact with the shelf after the cartridge is fully insertedinto the inhaler and retained by an end member of the inhaler. The shelfprovides precise and close positioning of the hollow needle relative toa vibratable membrane of the inhaler so that when a droplet of liquiddrug is dispensed via the hollow needle, surface tension will cause itto it will adhere to the vibratable membrane even when the inhaler is ina horizontal orientation. The adherence is controlled by the distancebetween the hollow needle and vibratable membrane, the inside diameterof the hollow needle, and the geometry of the hollow needle where thedroplet exits.

The membrane vibrates to generate an aerosol and creates a pumpingaction that pulls the droplet away from the hollow needle and throughthe membrane. At the end of a dose, there is no residual droplet to beaerosolized due to the pumping action of the membrane. In manyembodiments, elastomeric isolators are used to couple the vibratablemembrane with a housing of the inhaler to maximize efficiency of theaerosol generation.

The hollow needle can be coated, for example with silver, to discouragemicrobial ingress into the hollow needle and the liquid drug container.In many embodiments, there is no retrograde flow back into the containerafter a dose is dispensed (i.e., any drug in the needle stays there incontact with the antimicrobial coating to suppress pathogenproliferation). The self-puncturing liquid drug cartridge can include afilter configured to inhibit microbial ingress into the container.

The cartridge is configured to protect the user against accidentalneedle stick. Only one end of the hollow needle is sharpened and theguide element supports and encloses the hollow needle such that thesharp end of the hollow needle is not exposed and is directed towardsthe septum. The exposed end of the hollow needle is not sharpened. Aremovable protective cap protects the exposed end of the hollow needlefrom damage and contamination. The protective cap is shaped such thatthat the cartridge cannot be inserted into the inhaler until theprotective cap is removed.

The cartridge include a piston slidably disposed within the containerfor dispensing the liquid drug without the introduction of air. Thisfeature keeps the hollow needle submerged for the duration ofdispensing, improves physical stability of the drug product, supportsuse of the cartridge in a horizontal orientation, and maintains thecontainer in a sealed configuration at all times for consistent dosing.

The cartridge and the inhaler can be configured such that the cartridgecan be removed and reinserted at any time. For example, the cartridgecan be removed at any time to enhance access for cleaning the inhaler.In many embodiments, reinsertion of the cartridge induces a primingcycle. In such embodiments, the septum can be configured to be puncturedmultiple times without compromising the sterility of the container.

FIG. 9 illustrates a self-puncturing liquid drug cartridge 310, inaccordance with many embodiments. The cartridge 310 includes a containerassembly 312 and a needle assembly 314, which is coupled to thecontainer assembly 312 and includes a hollow needle 316.

The container assembly 312 is configured to store a liquid drug forsubsequent dispensing to an inhaler. The container assembly 312 includesa container 318 having openings at opposing ends of the container 318, aseptum 320 sealing a first end of the container 318, and a piston 322sealing a second end of the container 318. The septum 320 is configuredto be punctured by the hollow needle 316 to establish a fluid path bywhich the liquid drug within the container 318 can be dispensed to aninhaler. The piston 322 is selectively slidable within the container 318so as to eject a selected quantity of the liquid drug from the container318 via the hollow needle 316.

The needle assembly 314 is reconfigurable between a first configuration(illustrated in FIG. 9) in which the hollow needle 316 does not extendthrough the septum 320 and a second configuration (see, e.g., FIG. 13)in which the hollow needle 316 extends through the septum 320. Theneedle assembly 314 includes the hollow needle 316, a cap 324, a guideelement 326, and a spring 328. In the illustrated embodiment, the cap324 is configured to couple the needle assembly 314 to the containerassembly 312. Any suitable approach can be used to couple the needleassembly 314 with the container assembly 312. For example, in theillustrated embodiment, the cap 324 is configured to receive a first endportion of the container assembly 312 and retain the received portionvia complementary snap fit features of the cap 324 and the containerassembly 312. The guide element 326 includes a receptacle 330 configuredto slidingly receive and interface with the cap 324 and a portion of thecontainer assembly 312. Opposing ends of the spring 328 are coupled withan end wall 332 of the receptacle 330 and the cap 324, respectively. Inthe first configuration, the spring 328 is in an un-deflectedconfiguration and maintains the illustrated separation between the cap324 and the end wall 332 of the receptacle 330, thereby disposing thehollow needle 316 in the position illustrated relative to the septum320. The guide element 326 has an exterior surface 334 and an exteriorend wall surface 336.

FIG. 10 illustrates a removable protective cover 362 coupled with thecartridge 310. The protective cover 362 protects the hollow needle 316from damage and contamination. The cover 362 is shaped to preventinsertion of the cartridge 310 into the inhaler 40 until the cover 362is removed.

FIG. 11 illustrates the cartridge 310 partially inserted into theinhaler 40. As the cartridge 310 is inserted into the receptacle 48, thecartridge 310 remains in the first configuration in which the hollowneedle 316 does not extend through the septum 320 until the end wallexterior surface 336 contacts the shelf 52.

FIG. 12 illustrates the cartridge 310 almost fully inserted into theinhaler 40. In the illustrated configuration, the guide element 326 isin contact with the shelf 52 and the container assembly 312 has beenpushed towards the guide element 326, thereby partially compressing thespring 328 and inserting the sharpened end of the hollow needle 316through the septum 320. The force of the spring 328 holds the guideelement 326 in contact with the shelf 52, thereby fixing the position ofthe ejecting end of the hollow needle 316 relative to the vibratablemembrane 64 of the aerosol generator 44.

FIG. 13 illustrates the cartridge 310 fully inserted into the inhaler40. An end member 66 retains the cartridge 310 and reacts the forceimparted to the container assembly 312 via the compressed spring 328.The compressed spring 328 maintains the guide element 326 in contactwith the shelf 52, thereby maintaining a preferred predeterminedposition of the ejecting end of the hollow needle 316 relative to thevibratable membrane 64. While the sharpened end of the hollow needle 316is illustrated in FIG. 13 to be located a significant distance past theinner wall of the septum 320, in many embodiments the sharpened end ofthe hollow needle 316 is located closer to the septum 320 so as toincrease the amount of insulin that can be dispensed from the cartridge.

The inhaler 40 can include a suitable actuator for displacing the piston322 relative to the container 318 so as to eject a desired preselecteddose of liquid drug from the container 318 via the ejecting end of thehollow needle 316. For example, the end member 66 and the housing 42 canform a pressurizable vessel into which air can be injected so as todisplace the piston 322 towards the guide element 326. As anotherexample, the piston 322 can be controllably displaced toward the guideelement 326 via an actuation mechanism coupled with the end member 66 oracting through the end member 66.

In use, a user inhales from the mouthpiece 60 and the aerosol generator44 simultaneously aerosolizes a dose of liquid drug ejected from theejecting end of the hollow needle 316 via a corresponding actuation ofthe piston 322. The housing 42 includes one or more air inlets 68 and arestrictor array 70 by which air is introduced into a mixing chamber 72for combination with the aerosolized dose of the liquid drug prior toinhalation by the user.

As another example, a self-puncturing liquid drug cartridge can beconfigured similar to the cartridge 310 illustrated in FIG. 9, butwithout the spring 328. In such a configuration, the cartridge can bereconfigurable from a first configuration (similar to the firstconfiguration of the cartridge 310 illustrated in FIG. 9) in which thehollow needle 316 does not extend through the septum 320 and a secondconfiguration (similar to the second configuration of the cartridge 310illustrated in FIG. 13) in which the hollow needle extends through theseptum 320. For example, the cartridge can include one or more detentfeatures (e.g., one or more interfacing features of the guide element326 and the cap 324) that maintain the cartridge in the firstconfiguration prior to installation into an inhaler. Upon installationof the cartridge into an inhaler, the one or more detent features can beconfigured to permit relative movement between the guide element 326 andthe cap 326 in response to compression forces arising from theinstallation, thereby reconfiguring the cartridge into the secondconfiguration. In many embodiments without the spring 328, the cartridgeremains in the second configuration after being reconfigured into thesecond configuration. Additionally, one or more additional detentfeatures (e.g., one or more interfacing features of the guide element326 and the cap 324) that interface when the cartridge is in the secondconfiguration can be used to maintain the guide element 326 in contactwith the shelf 52, thereby maintaining a preferred predeterminedposition of the ejecting end of the hollow needle 316 relative to thevibratable membrane 64.

FIGS. 14 and 15 illustrates a self-puncturing liquid drug cartridge 430for use with the inhaler 40, in accordance with many embodiments. Thecartridge 430 includes a container assembly 412, a filter 416, a septum432, and a needle assembly 434, which is coupled to the containerassembly 412 and includes a hollow needle 436.

The container assembly 412 is configured to store a liquid drug forsubsequent dispensing to an inhaler. The container assembly 412 includesa container 418 having openings at opposing ends of the container 418,the filter 416, the septum 432 sealing a first end of the container 418,and a piston 420 sealing a second end of the container 418. The septum432 is configured to be punctured by the hollow needle 436 to establisha fluid path by which the liquid drug within the container 418 can bedispensed to an inhaler. The hollow needle 436 can penetrate partiallyinto the filter 416 so that the liquid drug passes through at least aportion of the filter 416 before entering the hollow needle 436. Thepiston 420 is selectively slidable within the container 418 so as toeject a selected quantity of the liquid drug from the container 418 viathe hollow needle 436.

The needle assembly 434 is reconfigurable between a first configuration(illustrated in FIG. 14) in which the hollow needle 436 does not extendthrough the septum 432 and a second configuration (see, e.g., FIG. 15)in which the hollow needle 436 extends through the septum 432. Theneedle assembly 434 includes the hollow needle 436, a cap 438, a guideelement 440, and a spring 442. In the illustrated embodiment, the cap438 is configured to couple the needle assembly 434 to the containerassembly 412. Any suitable approach can be used to couple the needleassembly 434 with the container assembly 412. For example, in theillustrated embodiment, the cap 438 is configured to receive a first endportion of the container assembly 412 and retain the received portionvia complementary snap fit features of the cap 438 and the containerassembly 412. The guide element 440 includes a receptacle 444 configuredto slidingly receive and interface with the cap 438 and a portion of thecontainer assembly 412. Opposing ends of the spring 442 are coupled withan end wall 446 of the receptacle 444 and the cap 438, respectively. Inthe first configuration, the spring 442 is in an un-deflectedconfiguration and maintains the illustrated separation between the cap438 and the end wall 446 of the receptacle 444, thereby disposing thehollow needle 436 in the position illustrated relative to the septum432. The guide element 440 has an exterior surface 448 and an exteriorend wall surface 450.

FIG. 14 illustrates the cartridge 430 partially inserted into theinhaler 440. As the cartridge 430 is inserted into the receptacle 448,the cartridge 430 remains in the first configuration in which the hollowneedle 436 does not extend through the septum 432 until the end wallexterior surface 450 contacts the shelf 52.

FIG. 15 illustrates the cartridge 430 fully inserted into the inhaler40. In the illustrated configuration, the guide element 440 is incontact with the shelf 52 and the container assembly 412 has been pushedtowards the guide element 440, thereby partially compressing the spring442 and inserting the sharpened end of the hollow needle 436 through theseptum 432. The force of the spring 442 holds the guide element 440 incontact with the shelf 52, thereby fixing the position of the ejectingend of the hollow needle 436 relative to the vibratable membrane 64 ofthe aerosol generator 44. An end member can be used to retain thecartridge 430 within the inhaler and react the force imparted to thecontainer assembly 412 via the compressed spring 442. The compressedspring 442 maintains the guide element 440 in contact with the shelf 52,thereby maintaining a preferred predetermined position of the ejectingend of the hollow needle 436 relative to the vibratable membrane 64.

The inhaler 40 can include a suitable actuator for displacing the piston420 relative to the container 418 so as to eject a desired preselecteddose of liquid drug from the container 418 via the ejecting end of thehollow needle 436. For example, an end member and the housing 42 canform a pressurizable vessel into which air can be injected so as todisplace the piston 420 towards the guide element 440. As anotherexample, the piston 420 can be controllably displaced toward the guideelement 440 via an actuation mechanism coupled with an end member oracting through the end member.

In use, a user inhales from the mouthpiece 60 and the aerosol generator44 simultaneously aerosolizes a dose of liquid drug ejected from theejecting end of the hollow needle 436 via a corresponding actuation ofthe piston 420. The housing 42 includes one or more air inlets 68 and arestrictor array 70 by which air is introduced into a mixing chamber 72for combination with the aerosolized dose of the liquid drug prior toinhalation by the user.

The specification and drawings are, accordingly, to be regarded in anillustrative rather than a restrictive sense. It will, however, beevident that various modifications and changes may be made thereuntowithout departing from the broader spirit and scope of the disclosure asset forth in the claims.

Other variations are within the spirit of the present disclosure. Thus,while the disclosed techniques are susceptible to various modificationsand alternative constructions, certain illustrated embodiments thereofare shown in the drawings and have been described above in detail. Itshould be understood, however, that there is no intention to limit thedisclosure to the specific form or forms disclosed, but on the contrary,the intention is to cover all modifications, alternative constructions,and equivalents falling within the spirit and scope of the disclosure,as defined in the appended claims.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the disclosed embodiments (especially in thecontext of the following claims) are to be construed to cover both thesingular and the plural, unless otherwise indicated herein or clearlycontradicted by context. The terms “comprising,” “having,” “including,”and “containing” are to be construed as open-ended terms (i.e., meaning“including, but not limited to,”) unless otherwise noted. The term“connected” is to be construed as partly or wholly contained within,attached to, or joined together, even if there is something intervening.Recitation of ranges of values herein are merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range, unless otherwise indicated herein and eachseparate value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein, isintended merely to better illuminate embodiments of the disclosure anddoes not pose a limitation on the scope of the disclosure unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe disclosure.

Disjunctive language such as the phrase “at least one of X, Y, or Z,”unless specifically stated otherwise, is intended to be understoodwithin the context as used in general to present that an item, term,etc., may be either X, Y, or Z, or any combination thereof (e.g., X, Y,and/or Z). Thus, such disjunctive language is not generally intended to,and should not, imply that certain embodiments require at least one ofX, at least one of Y, or at least one of Z to each be present.

Preferred embodiments of this disclosure are described herein, includingthe best mode known to the inventors for carrying out the disclosure.Variations of those preferred embodiments may become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theinventors expect skilled artisans to employ such variations asappropriate and the inventors intend for the disclosure to be practicedotherwise than as specifically described herein. Accordingly, thisdisclosure includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the disclosure unlessotherwise indicated herein or otherwise clearly contradicted by context.

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference were individually and specifically indicatedto be incorporated by reference and were set forth in its entiretyherein.

What is claimed is:
 1. A liquid drug cartridge, comprising: a containerconfigured to store a liquid drug; an end cap coupled with a first endof the container, the end cap having an ejection opening from which avolume of the liquid drug from the container can be selectively ejected;a filter element configured to filter the liquid drug prior to ejectionfrom the ejection opening; and a piston sealing a second end of thecontainer, the piston being repositionable relative to the container soas to selectively eject a volume of the liquid drug from the containervia the ejection opening.
 2. The cartridge of claim 1, wherein the endcap has a protruding portion in which the ejection opening is disposed.3. The cartridge of claim 2, further comprising a removable capconfigured to interface with the end cap so as to block flow of theliquid drug through the ejection opening.
 4. The cartridge of claim 1,wherein the end cap comprises a conduit in fluid communication with theejection opening for delivery of the liquid drug to the ejectionopening, the conduit being coated to inhibit microbial ingress into thecontainer.
 5. The cartridge of claim 4, wherein the conduit is coatedwith silver.
 6. The cartridge of claim 1, wherein the end cap comprisesa conduit in fluid communication with the ejection opening for deliveryof the liquid drug to the ejection opening, the conduit being configuredto inhibit escape of any amount of the liquid drug from the containerabsent repositioning of the piston relative to the container.
 7. Thecartridge of claim 6, wherein the conduit is coated to inhibit microbialingress into the container.
 8. The cartridge of claim 1, wherein thefilter is configured to inhibit microbial ingress into the container. 9.The cartridge of claim 1, wherein the cartridge is configured to inhibitescape of any amount of the liquid drug from the container absentrepositioning of the piston relative to the container.
 10. The cartridgeof claim 9, wherein the filter element is configured to inhibit escapeof any amount of the liquid drug from the container absent repositioningof the piston relative to the container.
 11. The cartridge of claim 1,wherein fluid is ejected from the cartridge in controlled doses bycontrolled movement of the piston.
 12. The cartridge of claim 11,wherein the size of each of the controlled doses is set via an externalcontrol.
 13. The cartridge of claim 11, wherein the cartridge contains aplurality of doses of medication and the medication can be deliveredfrom the cartridge in a plurality of individual doses.
 14. A liquid drugcartridge, comprising: a container configured to store a liquid drug; anend cap coupled with a first end of the container, the end cap having anejection opening from which a volume of the liquid drug from thecontainer can be selectively ejected; a check valve configured to permitone way flow from the container to the ejection opening to blockmicrobial ingress into the container from the ejection opening; and apiston sealing a second end of the container, the piston beingrepositionable relative to the container so as to selectively eject avolume of the liquid drug from the container via the ejection opening.15. An aerosolization system, comprising: an aerosol generator includinga vibratable membrane having a front face and a rear face, and avibratable element used to vibrate the membrane; a housing defining amouthpiece, the housing including a receptacle configured to at leastpartially receive a liquid drug cartridge and interface with the liquiddrug cartridge to position an ejection opening of the liquid drugcartridge to dispense liquid drug directly onto the rear face of thevibratable membrane to be aerosolized by controlled vibration of thevibratable element; and an actuator configured to reposition a piston ofthe liquid drug cartridge to dispense a dosage of the drug via theejection opening to the rear face of the vibratable membrane.
 16. Thesystem of claim 15, wherein the housing further includes: a mixingchamber in fluid communication with the front face of the vibratablemembrane and the mouthpiece; and one or more air inlets in fluidcommunication with the mixing chamber and configured to inlet air intothe mixing chamber in response to a user inhaling via the mouthpiece.17. The system of claim 16, further comprising an air flow restrictorarray having greater resistance to air flow than the one or more airinlets and placing the mixing chamber in fluid communication with theone or more air inlets.
 18. The system of claim 17, wherein air flowingthrough the mixing chamber in response to the user inhaling via themouthpiece is laminar and surrounds a dosage of the drug aerosolized viathe vibratable membrane so as to inhibit contact between the aerosolizeddrug and surrounding surfaces of the mixing chamber.
 19. The system ofclaim 18, further comprising a pressure port connected to a pressuresensing system, wherein a patient's inhalation is detected via thepressure port.
 20. The system of claim 17, wherein the airflowrestrictor array comprises a plurality of orifices disposed in anannular arrangement.
 21. The system of claim 15, further comprising: oneor more processors; a tangible memory storing non-transitoryinstructions that, when executed by the one or more processors, causethe one or more processors to control the actuator to reposition thepiston relative to the container until a drop of the liquid drug isejected from the ejection opening.
 22. The system of claim 21, whereinthe instructions, when executed by the one or more processors, cause theone or more processors to determine that a drop of the liquid drug hasbeen ejected from the ejection opening by detecting when the vibratablemembrane has been wetted by the ejected drop of the liquid drug.
 23. Thesystem of claim 15, wherein the cartridge is configured to be removed atany time to enable more thorough cleaning of the dispenser.
 24. Thesystem of claim 15, wherein: the cartridge includes a removable capconfigured to interface with the end cap so as to block flow of theliquid drug through the ejection opening; and the removable cap isconfigured such that the cartridge cannot be inserted into thereceptacle until the cap is removed from the cartridge.
 25. The systemof claim 15, wherein the vibratable mesh is coupled with the housing viaelastomeric isolators configured to enhance efficiency of the aerosolgenerator.
 26. The system of claim 15, further comprising an ultravioletlight configured to provide microbial control between doses.
 27. Thesystem of claim 15, wherein: the housing forms a pressurizable vessel;and the actuator pressurizes the vessel to reposition the pistonrelative to the container to dispense a dosage of the drug via theejection opening to the rear face of the membrane.
 28. The system ofclaim 15, wherein the actuator mechanically displaces the pistonrelative to the container so as to dispense a predetermined desiredamount of the liquid drug via the ejection opening.
 29. The system ofclaim 28, wherein the actuator further comprising an adjustable meteringmechanism that is operable to permit only selectable amounts ofrepositioning of the piston relative to the container so that aselectable dosage of the liquid drug is dispensed.